For COVID-19 vaccine updates, please review our information guide. For patient eligibility and scheduling availability, please visit VaccineTogetherNY.org.

A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells.

TitleA novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsZhang Y, Lv D, Kim H-J, Kurt RA, Bu W, Li Y, Ma X
JournalCell Res
Volume23
Issue3
Pagination394-408
Date Published2013 Mar
ISSN1748-7838
KeywordsAnimals, Antibodies, Neutralizing, Bone Marrow Transplantation, CD11b Antigen, CD8-Positive T-Lymphocytes, Cells, Cultured, Chemokine CCL5, Disease Progression, Humans, Male, Mammary Neoplasms, Animal, Mice, Mice, Inbred BALB C, Mice, Knockout, Myeloid Cells, T-Lymphocytes, Cytotoxic
Abstract

CCL5 is a member of the CC chemokine family expressed in a wide array of immune and non-immune cells in response to stress signals. CCL5 expression correlates with advanced human breast cancer. However, its functional significance and mode of action have not been established. Here, we show that CCL5-deficient mice are resistant to highly aggressive, triple-negative mammary tumor growth. Hematopoietic CCL5 is dominant in this phenotype. The absence of hematopoietic CCL5 causes aberrant generation of CD11b(+)/Gr-1(+), myeloid-derived suppressor cells (MDSCs) in the bone marrow in response to tumor growth by accumulating Ly6C(hi) and Ly6G(+) MDSCs with impaired capacity to suppress cytotoxicity of CD8(+) T cells. These properties of CCL5 are observed in both orthotopic and spontaneous mammary tumors. Antibody-mediated systemic blockade of CCL5 inhibits tumor progression and enhances the efficacy of therapeutic vaccination against non-immunogenic tumors. CCL5 also helps maintain the immunosuppressive capacity of human MDSCs. Our study uncovers a novel, chemokine-independent activity of the hematopoietically derived CCL5 that promotes mammary tumor progression via generating MDSCs in the bone marrow in cooperation with tumor-derived colony-stimulating factors. The study sheds considerable light on the interplay between the hematopoietic compartment and tumor niche. Because of the apparent dispensable nature of this molecule in normal physiology, CCL5 may represent an excellent therapeutic target in immunotherapy for breast cancer as well as a broad range of solid tumors that have significant amounts of MDSC infiltration.

DOI10.1038/cr.2012.178
Alternate JournalCell Res
PubMed ID23266888
PubMed Central IDPMC3587709
Grant ListR01 CA124820 / CA / NCI NIH HHS / United States
CA124820 / CA / NCI NIH HHS / United States

Weill Cornell Medicine Microbiology and Immunology 1300 York Avenue, Box 62 New York, NY 10065 Phone: (212) 746-6505 Fax: (212) 746-8587